TY - JOUR

T1 - Clinical and genetic characterization of patients segregating variants in KPTN, MINPP1, NGLY1, AP4B1, and SON underlying neurodevelopmental disorders

T2 - Genetic and phenotypic expansion

AU - Ullah, Asmat

AU - Shah, Abid Ali

AU - Alluqmani, Majed

AU - Haider, Nighat

AU - Aman, Hasan

AU - Alfadhli, Fatima

AU - Almatrafi, Ahmad M.

AU - Albalawi, Alia M.

AU - Krishin, Jai

AU - Ullah Khan, Fati

AU - Anjam, Bilal Ali

AU - Abdullah, null

AU - Lozano, Elionora Peña

AU - Samad, Abdus

AU - Ahmad, Wasim

AU - Hansen, Torben

AU - Xia, Kun

AU - Basit, Sulman

N1 - Publisher Copyright: © 2022 International Society for Developmental Neuroscience.

PY - 2022

Y1 - 2022

N2 - Neurodevelopmental disorders (NDDs) are heterogeneous genetic conditions of the central nervous system (CNS). Primary phenotypes of NDDs include epilepsy, loss of developmental skills, abnormal movements, muscle weakness, ocular anomalies, hearing problems, and macro- or microcephaly. NDDs occur due to variants in genes encoding proteins involved in the structure and function of CNS, thus interrupting its normal physiological role. In the study presented here, four consanguineous families (A–D), with members showing neurodevelopmental symptoms, were recruited for clinical and genetic characterization of the phenotypes. Clinical examinations, including Seguin Form Board Test (SFBT), Vineland Social Maturity Scale (VSMS), brain Magnetic Resonance Imaging (MRI), Electroencephalogram (EEG), Electromyography (EMG), Nerve Conduction Velocity (NCV), and Magnetic Resonance Spectroscopy, were employed to characterize the disease phenotypes. Whole exome sequencing (WES) followed by Sanger sequencing was employed to search for the genetic basis of the neurological symptoms observed in four families (A–D). Two of these families (A, B) were of Saudi Arabian origin, and two others (C, D) were of Pakistan origin. Two homozygous missense (KPTN: NM_007059.4:c.301T>G: NP_008990.2; p.(Phe101Val) and MINPP1:NM_001178118.2:c.1202G>A: NP_001171588.1; p.(Arg401Gln)) variants in families A and B, respectively, and two homozygous nonsense (NGLY1:NM_018297.3:c.1534_1541dup: NP_060767.2; p.(Ser515LysfsTer51) and AP4B1:NM_001253852:c.1668G>A: NP_001240781.1; p.(Trp556X)) variants in families C and D, respectively, were identified. Interestingly, additional heterozygous nonsense variant in SON: NM_138927.2: c.5753_5756del: NP_620305.3; p.(Val1918GlufsTer87) and a homozygous variant in FLG (FLG: NM_002016.2:c.7339C>T: NP_002007.1; p.(Arg2447X) were detected in families A and D, respectively. Further, we determined the deleteriousness of each variant through computational approaches. The present study expands the phenotypic and genetic spectrum of NDD-associated genes (KPTN, MINPP1, NGLY1, and AP4B1). Moreover, additional nonsense variants (SON: c.5753_5756del and FLG: c.7339C>T) identified in two families segregating with the phenotype might explain the phenotypic variability and severity in our patients.

AB - Neurodevelopmental disorders (NDDs) are heterogeneous genetic conditions of the central nervous system (CNS). Primary phenotypes of NDDs include epilepsy, loss of developmental skills, abnormal movements, muscle weakness, ocular anomalies, hearing problems, and macro- or microcephaly. NDDs occur due to variants in genes encoding proteins involved in the structure and function of CNS, thus interrupting its normal physiological role. In the study presented here, four consanguineous families (A–D), with members showing neurodevelopmental symptoms, were recruited for clinical and genetic characterization of the phenotypes. Clinical examinations, including Seguin Form Board Test (SFBT), Vineland Social Maturity Scale (VSMS), brain Magnetic Resonance Imaging (MRI), Electroencephalogram (EEG), Electromyography (EMG), Nerve Conduction Velocity (NCV), and Magnetic Resonance Spectroscopy, were employed to characterize the disease phenotypes. Whole exome sequencing (WES) followed by Sanger sequencing was employed to search for the genetic basis of the neurological symptoms observed in four families (A–D). Two of these families (A, B) were of Saudi Arabian origin, and two others (C, D) were of Pakistan origin. Two homozygous missense (KPTN: NM_007059.4:c.301T>G: NP_008990.2; p.(Phe101Val) and MINPP1:NM_001178118.2:c.1202G>A: NP_001171588.1; p.(Arg401Gln)) variants in families A and B, respectively, and two homozygous nonsense (NGLY1:NM_018297.3:c.1534_1541dup: NP_060767.2; p.(Ser515LysfsTer51) and AP4B1:NM_001253852:c.1668G>A: NP_001240781.1; p.(Trp556X)) variants in families C and D, respectively, were identified. Interestingly, additional heterozygous nonsense variant in SON: NM_138927.2: c.5753_5756del: NP_620305.3; p.(Val1918GlufsTer87) and a homozygous variant in FLG (FLG: NM_002016.2:c.7339C>T: NP_002007.1; p.(Arg2447X) were detected in families A and D, respectively. Further, we determined the deleteriousness of each variant through computational approaches. The present study expands the phenotypic and genetic spectrum of NDD-associated genes (KPTN, MINPP1, NGLY1, and AP4B1). Moreover, additional nonsense variants (SON: c.5753_5756del and FLG: c.7339C>T) identified in two families segregating with the phenotype might explain the phenotypic variability and severity in our patients.

U2 - 10.1002/jdn.10231

DO - 10.1002/jdn.10231

M3 - Journal article

C2 - 36181241

AN - SCOPUS:85139552537

VL - 82

SP - 788

EP - 804

JO - International Journal of Developmental Neuroscience

JF - International Journal of Developmental Neuroscience

SN - 0736-5748

IS - 8

ER -